Pharmacokinetics Of Florfenicol Sustained-Release Microcapsules In Pigs And An In Vitro-in Vivo Correlation Study

In this study,the in vitro release of florfenicol sustained-release microcapsules and comparative pharmacokinetics of florfenicol sustained-release microcapsules and florfenicol powder in pigs were studied.The comparison of pharmacokinetic parameters and the analysis of the in vitro and in vivo correlations of sustained-release microcapsules will provide a reference for the further development and clinical application of florfenicol sustained-release microcapsules.The in vitro release test method of florfenicol was refering to the"Chinese Veterinary Pharmacopoeia"（2015 version）the first method of release measurement method（basket method）,at a speed of 100 r/min,37℃±0.5℃,p H1.2 Hydrochloric acid solution,p H4.3acetate buffer solution（containing 0.5%SDS）and p H6.8 phosphate buffer solution（containing 0.5%SDS）are the release media.After sampling at different time points,the content was determined by HPLC-UV method,and the cumulative release of the florfenicol preparation at different time points was calculated.Origin Pro8.0 was used to fit the zero-order equation,First-order equation and Higuchi equation to the cumulative drug release-time data.The results showed that the cumulative release of florfenicol sustained-release granules in p H 1.2 hydrochloric acid solution was 11.18%～13.43%within 4 h;in p H 4.3 acetate buffer（containing 0.5%SDS）and p H 6.8 phosphate buffer（With 0.5%SDS）slowly and completely released within 8 hours without burst release.Thirty-two pigs were randomly divided into 4 groups with 8 animals in each group.They were respectively fed with 10%florfenicol sustained-release microcapsules,10%florfenicol powder and 5%florfenicol injection intravenously,all given as a single dose of20 mg/kg b.w.After 14 days of single-dose administration,7 pigs were randomly selected from 32 pigs to conduct a multi-dose study of sustained-release microcapsules.Plasma samples were detected by HPLC-UV method,and the pharmacokinetic parameters were calculated using Winnonlin 5.2.1 software non-compartment model.The main pharmacokinetic parameters of the mixed-feeding oral florfenicol sustained-release microcapsule group are as follows:the area under the drug-time curve（AUC）is 58.410±9.436 h·μg/m L,and the average residence time（MRT）is 8.919±0.773 h,the elimination half-life(t_1/2)is 5.480±0.508 h,the peak time(T_max)is 3.625±0.518 h,and the peak concentration(C_max)is 5.622±0.580μg/m L.The main pharmacokinetic parameters of the florfenicol powder group were as follows:the area under the drug-time curve（AUC）was 100.885±9.355 h·μg/m L,and the average residence time（MRT）was 5.595±0.493 h,eliminating half-life(t_1/2)was 3.534±0.313 h,peak time(T_max)was 1.406±0.533 h,and peak concentration(C_max)was 15.049±1.832μg/m L.The main pharmacokinetic parameters of the florfenicol sustained-release microcapsule group were as follows:the area under the drug-time curve（AUC）was66.568±8.876 h·μg/m L,and the average residence time（MRT）was 9.178±1.165 h,The elimination half-life(t_1/2)was 5.125±0.861 h,the peak time(T_max)was 4.00±0.926 h,and the peak concentration(C_max)was 6.367±1.279μg/m L.The main pharmacokinetic parameters of the intravenous florfenicol injection group are as follows:the area under the drug-time curve（AUC）is 104.814±11.626 h±μg/m L,and the apparent volume of distribution（Vd）is 0.943±0.064 m L/kg,body clearance rate（CL）is0.193±0.022 m L/h/kg,elimination half-life(t_1/2)is 3.418±0.382 h,and peak concentration(C_max)is 25.028±2.075μg/m L.The sustained-release microcapsule multi-dose blood drug steady-state trough concentration Cssmin was 4.093±0.386μg/m L,and the blood drug steady-state peak concentration Cssmax was 6.589±0.669μg/m L.Comparing the pharmacokinetic parameters,the T_max of delayed-release microcapsules was significantly delayed compared with the oral powder.The C_max was significantly reduced.The t_1/2 was significantly increased,with Vd Significantly increasing and F decreasing by 32.76%.And the statistical analysis showed that the T_max,C_max,Vd and t_1/2 of the sustained-release microcapsule group and the powder group were significantly different（P<0.01）,indicating that the sustained-release microcapsules in this experiment prolonged the release time of drugs in the intestine,reduced the peak concentration of blood drugs,and widely distributed in the body.The blood concentration of multi-dose administration showed that the sustained-release microcapsules can maintain a stable concentration under normal administration.The decrease in peak concentration and the decrease in absolute bioavailability indicated that the sustained-release microcapsules may have better safety than powders.Linear regression was performed on the percentage of in vitro release and in vivo absorption of microcapsules,and the correlation coefficients of the regression equation were greater than their critical correlation coefficients,indicating that the microcapsules had good in vitro and in vivo correlations in different release media,including p H 1.2hydrochloric acid.The in vivo and in vitro regression equations of the slow-release microcapsules in the buffer solution have the largest correlation coefficients and the strongest in vivo and in vitro correlations.